Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking

Maza, Nycole A.; Wang, Dandan; Kowalski, Cody; Stoveken, Hannah M.; Dao, Maria; Sial, Omar K.; Giles, Andrew C.; Grill, Brock; Martemyanov, Kirill A.

doi:10.1038/s41593-022-01135-0

Cited by 10 publications

(5 citation statements)

References 60 publications

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“…For PTCHD1 , knock-out in mice results in behavioral and electrophysiological alterations 27, 34, 35 . Moreover, loss of PTCHD1 impairs cholesterol-dependent μ-opioid receptor trafficking and function 36 . However, it is unknown whether loss of Ptchd1 affects cholesterol homeostasis in vivo .…”

Section: Resultsmentioning

confidence: 99%

“…SCAP is involved in cholesterol biosynthesis regulation where it acts as cholesterol sensor 53 . Notably, a recent study linked PTCHD1 and plasma membrane cholesterol to μ-opioid receptor trafficking 36 . Thus, it might be of interest to further investigate sterol-sensing and cholesterol-dependent trafficking functions of PTCHD1 in the future.…”

Section: Discussionmentioning

confidence: 99%

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Cell type-specific assessment of cholesterol distribution in models of neurodevelopmental disorders

Czernecki

Dixit

Riezman³

et al. 2022

Preprint

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Most nervous system disorders manifest through alterations in neuronal signaling based on abnormalities in neuronal excitability, synaptic transmission, and cell survival. However, such neuronal phenotypes are frequently accompanied or even caused by metabolic dysfunctions in neuronal or nonneuronal cells. The tight packing and highly heterogenous properties of neural, glial and vascular cell types pose significant challenges to dissecting metabolic aspects of brain disorders. Perturbed cholesterol homeostasis has recently emerged as key parameter associated with sub-sets of neurodevelopmental disorders. However, approaches for tracking and visualizing endogenous cholesterol distribution in the brain have limited capability of resolving cell type-specific differences. We here develop tools for genetically-encoded sensors that report on cholesterol distribution in the mouse brain with cellular resolution. We apply these probes to examine sub-cellular cholesterol accumulation in two genetic mouse models of neurodevelopmental disorders, Npc1 and Ptchd1 knock-out mice. While both genes encode proteins with sterol-sensing domains that have been implicated in cholesterol transport, we uncover highly selective and cell type-specific phenotypes in cholesterol homeostasis. The tools established in this work should facilitate probing sub-cellular cholesterol distribution in complex tissues like the mammalian brain and enable capturing cell type-specific alterations in cholesterol flow between cells in models of brain disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cell type-specific assessment of cholesterol distribution in models of neurodevelopmental disorders

Czernecki

Dixit

Riezman³

et al. 2022

Preprint

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“…GPCRs are targeted by more than 30% of approved drugs, modulating their internalization processes may maximize therapeutic efficacy and minimize adverse envents 8, 57 . Here, we provide an unprecedented description of 60 GPCR internalization profiles, including both constitutive and agonist-induced internalization in the absence and presence of βarrs.…”

Section: Discussionmentioning

confidence: 99%

Multi-faceted roles of β-arrestins in G protein-coupled receptors endocytosis

Liu,

Xue,

Ravier

et al. 2024

Preprint

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Internalization plays a crucial role in regulating the density of cell surface receptors and has been demonstrated to regulate intracellular signaling. Dysregulation of this process has been implicated in various diseases. The vast majority of GPCRs were considered to adopt one way for internalization. We challenged this conventional view by showing that multiple pathways converge to regulate the internalization of a specific receptor, based on an unparalleled characterization of 60 GPCR internalization profiles, both in the absence and presence of individual βarrestins (βarrs). Furthermore, we revealed the internalization mechanism of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR pivotal in promoting insulin secretion from pancreatic beta cells to maintain glucose homeostasis. GLP-1R can undergo agonist-induced internalization without βarrs, but can recruit and form stable complexes with βarrs. We found that GLP-1R recruits clathrin adaptor protein-2 for agonist-induced internalization in both βarr-dependent and -independent manners. These results provide a valuable resource for GPCR signaling and reveal the plasticity of different GPCRs to employ or not βarrs in the clathrin-mediated internalization.

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“…Allosteric modulators have been proposed to bind to multiple other cholesterol binding sites on hCB 1 [ 22 , 27 ]. Membrane cholesterol has been suggested to be a key mediator of GPCR signalling, specifically regarding the development of tolerance to therapeutic effects [ 28 ]. This indicates that the role of cholesterol in allosteric modulation of hCB 1 should be further investigated, specifically whether hCB 1 allosteric ligands compete with endogenous cholesterol for cholesterol binding sites.…”

Section: Discussionmentioning

confidence: 99%

Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies

Green,

Fellner,

Finlay

et al. 2024

Pharmaceuticals

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Positive allosteric modulators (PAMs) of the cannabinoid CB1 receptor (CB1) offer potential therapeutic advantages in the treatment of neuropathic pain and addiction by avoiding the adverse effects associated with orthosteric CB1 activation. Here, molecular modeling and mutagenesis were used to identify residues central to PAM activity at CB1. Six putative allosteric binding sites were identified in silico, including novel sites previously associated with cholesterol binding, and key residues within each site were mutated to alanine. The recently determined ZCZ011 binding site was found to be essential for allosteric agonism, as GAT228, GAT229 and ZCZ011 all increased wild-type G protein dissociation in the absence of an orthosteric ligand; activity that was abolished in mutants F191A3.27 and I169A2.56. PAM activity was demonstrated for ZCZ011 in the presence of the orthosteric ligand CP55940, which was only abolished in I169A2.56. In contrast, the PAM activity of GAT229 was reduced for mutants R220A3.56, L404A8.50, F191A3.27 and I169A2.56. This indicates that allosteric modulation may represent the net effect of binding at multiple sites, and that allosteric agonism is likely to be mediated via the ZCZ011 site. This study underlines the need for detailed understanding of ligand receptor interactions in the search for pure CB1 allosteric modulators.

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Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking

Cited by 10 publications

References 60 publications

Cell type-specific assessment of cholesterol distribution in models of neurodevelopmental disorders

Cell type-specific assessment of cholesterol distribution in models of neurodevelopmental disorders

Multi-faceted roles of β-arrestins in G protein-coupled receptors endocytosis

Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies

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